Transcript Wilms tumor
WT1: Wilms’ Tumor gene by Jennifer Mackey Kidney MRI (Scott et al., 2001) Wilms’ Tumor o NEPHROBLASTOMA in children o Discovered by Max Wilms in 1899 oWT1 is a tumor suppressor o10-15% due to WT1 inactivation BUT, MUTATED WT1 IS ALSO FOUND IN OTHER CANCERS!! BUT, MUTATED WT1 IS ALSO FOUND IN OTHER CANCERS!! AND AS WE WILL SEE - IT IS NOT ALWAYS A TUMOR SUPPRESSOR!!! WT1 is alternatively spliced to make many protein isoforms (Wagner, K.D. et al., 2003) WT1 is a transcription factor (Exon 5) (Exon 9) (Scholz, H. et al., 2005) WT1 is a transcription factor Target Growth factor Amphiregulin Insulin growth factor II Platelet derived growth factor Transforming growth factor-beta Receptors Androgen receptor Epidermal growth factor receptor Insulin receptor Insulin growth factor – I receptor Transcription factor c-Myc Cyclin E Cyclin G1, IGFBP-4 P21 Pax-2 Enzymes Effect Activation Activation/repression Repress/act Repression Repression Repression Repression Repression Activation/repression Repression Activation Activation Repression Human telomerase reverse transcriptase Repression Ornithine decarboxylase ECM E-cadherin Syndecan-1 Other Wnt-4 Repression Bcl-2 Activation/repression Increased Activation Activation WT1’s normal biological functions o o o o o Development of genitourinary system Development of kidney Adult kidney Heart development Neuron development? WT1-/• dies E12-birth • no kidneys • no gonads •severe abnormalities of retinal development wt KO (Kreidberg et al., 1993) WT1-/• dies E12-birth • no kidneys • no gonads •severe abnormalities of retinal development WT1+/• increased mortality due to adult onset nephrotic syndrome & renal failure WT1 is required for kidney development (Scholz, H. et al., 2005) ADULT KIDNEY http://en.wikipedia.org/wiki/Image:Gray1128.png WT1 is part of a transcriptional regulatory network That is critical for kidney development (Scharnhorst, V. et al., 2001) WT1 is part of a transcriptional regulatory network That is critical for kidney development (Scharnhorst, V. et al., 2001) WT1 TARGET GENES INVOLVED IN KIDNEY DEVELOPMENT: Amphiregulin: stimulates uretic bud BCL-2: encodes antiapoptotic protein E-cadherin: mesenchyme condensation REMEMBER: WT1 = differentiation WT1 = PROLIFERATION!! Wilms tumor • Most are sporadic and unilateral • 10-15% of sporadic have WT1 inactivation • Most others have high levels of WT1 expression • ~10% are bilateral and/or multifocal http://www.sainte-justine.org/ Wilms tumor • Most are sporadic and unilateral • 10-15% of sporadic have WT1 inactivation • Most others have high levels of WT1 expression • ~10% are bilateral and/or multifocal WAGR (Wilms’ tumor, Aniridia, Genitourinary abnormalities, Mental retardation) • Germline deletion • Predisposition to WT http://en.wikipedia.org/wiki/Image:BlackEyesAniridia.jpg Wilms tumor • Most are sporadic and unilateral • 10-15% of sporadic have WT1 inactivation • Most others have high levels of WT1 expression • ~10% are bilateral and/or multifocal WAGR (Wilms’ tumor, aniridia, genitourinary abnormalities, mental retardation) • Germline deletion • Predisposition to WT Denys-Drash Syndrome (DDS) • Germline mutations (missense mutation in zinc finger domain) • Dominant-negative activity • Predisposition to WT Wilms tumor • Most are sporadic and unilateral • 10-15% of sporadic have WT1 inactivation • Most others have high levels of WT1 expression • ~10% are bilateral and/or multifocal WAGR (Wilms’ tumor, aniridia, genitourinary abnormalities, mental retardation) • Germline deletion • Predisposition to WT Denys-Drash Syndrome (DDS) • Germline mutations (missense mutation in zinc finger domain) • Dominant-negative activity • Predisposition to WT Frasier Syndrome •Germline point mutation in the intron 9 donor splice site •Loss of KTS (-) = ratio disturbed •WT very rare! Acute myeloid leukemia(AML): WT1 overexpressed in leukemic blasts http://en.wikipedia.org/wiki/Image:Auer_rods.PNG Acute myeloid leukemia(AML): WT1 overexpressed in leukemic blasts Breast cancer: expression of WT1 detected in majority of BC’s evaluated www.hopeforcancer.com/BreastCancer.html Acute myeloid leukemia(AML): WT1 overexpressed in leukemic blasts Breast cancer: expression of WT1 detected in majority of BC’s evaluated Renal cell carcinoma: overexpression of WT1 in tubular epithelial cells in adulthood http://en.wikipedia.org/wiki/Image:RCC.jpg 80% of tumors can be treated successfully!!! REFERENCES Kreidberg, Jordan A. et al. 1993. WT-1 Is Required for Early Kidney Development. Cell 74: 679-691. Loeb, David M. and Saraswati Sukumar. 2002. The Role of WT1 in Oncogenesis: Tumor Suppressor or Oncogene? International Journal of Hematology 76: 117-126. Scharnhorst, Volkher et al. 2001. WT1 proteins: functions in growth and differentiation. Gene 273: 141-161. Scholz, Holger and Karin M. Kirschner. 2005. A Role for the Wilms’ Tumor Protein WT1 in Organ Development. Physiology 20: 54-59. Scott, Carly M. et al. 2001. Wilms' Tumor: A Primary Care Case Study And Differential Diagnosis. The Internet Journal of Advanced Nursing Practice 5: Number 1. Wagner, K-D et al. 2003. The complex life of WT1. Journal of Cell Science 116: 1653-1658. Wagner et al. 2006. Intermediate filament protein nestin is expressed in developing kidney and heart and might be regulated by the Wilms’ tumor suppressor WT1. American Journal of Physical Regul Integr Comp Physiology 291: R779-R787.